Ensartinib Receives FDA Approval for ALK-Positive Lung Cancer

On 18 December 2024, the US Food and Drug Administration (FDA) approved ensartinib (Ensacove, Xcovery Holdings, Inc.) for adults who had not previously received ALK inhibitor therapy and had anaplastic lymphoma kinase (ALK)-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).

ALK (anaplastic lymphoma kinase) receptor is encoded in humans by the ALK gene and is responsible for growth and proliferation. ALK can trigger lung cancer when its gene fuses with the EML4 gene (a fusion). This is one of the major causes of lung cancer in nonsmokers.

How Common Is ALK Positivity in Lung Cancer?

The EML4-ALK fusion gene in non-small cell lung cancer (NSCLC) is responsible for approximately 5% of cases. This may seem a small proportion, but given that lung cancer is the most common cancer worldwide, it corresponds to 70 thousand new patients with lung cancer each year.

Ensartinib Is the 6th Drug to Receive FDA Approval for ALK-Positive Lung Cancer

For ALK-positive lung cancer, the first FDA approval was for Xalkori, containing crizotinib, in 2011. Over the following years, 4 other ALK inhibitors received FDA approval: ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena). Ensacove, containing ensartinib, became the 6th FDA-approved ALK inhibitor.

FDA Approval Based on the eXALT3 Study

Ensartinib's efficacy and safety were evaluated in an open-label, randomized, active-controlled, multicenter study called eXALT3. It included 290 patients with ALK-positive locally advanced or metastatic NSCLC who had not previously received ALK-targeted treatment. Patients were randomized 1:1 to ensartinib or crizotinib.

• Primary Efficacy Endpoint: Progression-free survival (PFS), assessed by independent central review.
• Secondary Efficacy Endpoint: Overall survival.

Ensartinib produced a statistically significant improvement in progression-free survival compared with crizotinib:

• Median PFS in the ensartinib arm was 25.8 months (95% CI: 21.8, not estimable), compared with a median PFS of 12.7 months (95% CI: 9.2, 16.6) in the crizotinib arm.
• Ensartinib reduced the risk of cancer progression by 44% (HR: 0.56; 95% CI: 0.40, 0.79; p=0.0007).

However, there was no statistically significant difference in overall survival between the two treatment groups:

• Ensartinib reduced the risk of death by 12% (HR: 0.88; 95% CI: 0.63, 1.23; p=0.4570).

Adverse Effects and Safety

The most common adverse effects during ensartinib treatment (in 20% or more) were:

• Skin rash,
• Musculoskeletal pain,
• Constipation,
• Cough,
• Itching,
• Nausea,
• Edema,
• Fever,
• Fatigue.

Recommended Dose

The recommended dose of ensartinib is 225 mg once daily, with or without food. Treatment should continue until disease progression or an unacceptable adverse effect occurs.

Conclusion and Significance

Ensartinib offers an effective treatment option for ALK-positive non-small cell lung cancer, providing an important advantage particularly in progression-free survival. However, its limited effect on overall survival highlights the need for further studies of combination or sequential treatments for these cancers.

Drugs developed against the ALK-EML4 fusion mutation, an important target in lung cancer—in other words,  treatments for ALK-positive lung cancer —can be seen below.

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